Novel 4-chloro-delta4, 9, 11-gonatrienes



United States Patent The invention relates to novel 4-chloro-A -gonatricues of the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbonatoms, R is the methyl radical, R is selected from the group consisting of hydrogen and a lower alkyl radical and to a novel process for their preparation.

The compounds of Formula I possess an interesting physiological activity, particularly a strong anabolic activity in warm-blooded animals. For example, 4 chloro 17B acetoxy 135 methyl A4311 gonatriene-B-one has an anabolic activity almost 20 times greater than 4-chloro-19-nor-testosterone and an anabolic activity distinctly superior to l7fi-acetoxy-l3fi-methyl- A -gonatriene-one as well as having about 50% less androgenic activity as determined on genital organs of test animals.

4 chloro 13,8,17m dimethyl A4911 gonatrienel7fi-ol-3-one has a very important anabolic activity.

It is an object of the invention to provide novel 4-chloro-A gonatriene of Formula I.

It is another object of the invention to provide a novel process for the preparation of 4-chlor0-A l-gonatriene of Formula I. v

These and other objects and advantages of the invention will become obvious from the following detailed description.

The novel 4-chloro-A -g0natrienes of the invention have the formula wherein R is selected from the group consisting of hydrogen and an acyl radical of an organic carboxylic acid having 1 to 18 carbon atoms, R, is the methyl radical, R is selected from the group consisting of hydrogen and a lower alkyl radical.

The acyl radical of the organic carboxylic acid having 1 to 18 carbon atoms may be derived from an aliphatic, aromatic, cycloaliphatic or heterocyclic carboxylic acid. Examples of suitable acids are alkanoic acids such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic 3,309,388 Patented Mar. 14, 1967 acid, caproic acid, fl-trimethyl propionic acid, heptanoic acid, caprylic acid, pelargin-ic acid, capric acid, undecylic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids such as undecylenic acid and oleic acid; cycloalkylcarboxylic acids such as cyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexyl carboxylic acid, cycloalkyl alkanoic acids such as cyclopentyl acetic acid, cycloh'exyl acetic acid, cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids such as phenyl acetic acids and phenyl propionic acid; aryl carboxylic acids such as benzoic acid and 2,4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxy acetic acid, p-chloroacetic acid, 2,4-dichlorophenoxy acetic acid, 4-tert.butylphenoxy acetic acid, 3-phenoxy butyric acid; heterocyclic carboxylic acids such as furane-2-carboXyl-ic acid, 5-tert.- butylfurane-Z-carboxylic acid, S-bromofurane-Z-carboxylic acid and nicotinic acids; fl-ketoalkanoic acids, such as acetylacetic acid, propionylacetic acid and butyrylacetic acid; amino acids such as diethylaminoacetic acid and aspartic acid.

The novel process of the invention for the preparation of 4-chlor0-A -gonatrienes of Formula I which comprises reacting a 17,8-OR-l3,Q-R 17aR -A gonatriene-3-one of formula vone. A preferred mode of chlorinating is with sulfuryl chloride, preferably in the presence of a tertiary base such as pyridine or with tert.-butyl hypochlorite in the presence of acetic acid in acetic acid anhydride. The chlorination is usually affected at or near room temperature.

gonatriene-Ii-one, may be prepared by the process of commonly assigned, copending application Ser. No. 397,628, filed Sept. 18, 1964, now US. Pat No, 3,248,294 which comprises reacting 3-chloro-13fi-R -l7fi-OR'-4,S- secQ-A -gOnadiene-S-one wherein R' is an acyl radical of an organic carboxylic acid of l to 18 carbon atoms with an acetic acid esterifying agent under acid conditions to form 3-chloro-5-acetoxy-13 8-R -17B-OR'4,5- seco-A l-gonatriene, brominating the latter in the presence of a tertiary base to form 3-chloro-ll-bromo- 13fi-R -17B-OR-4,5-seco-A -gonadiene-5-one, dehydrobrominating the latter to form 3-chloro-l3;3-R -17/3-OR'- 4,5-seco-A -gonatriene-3-one,' hydrolyzing the latter under acid conditions to form 13B-R -17fi-OR'-4,5-seco- A -gonadiene-B,S-dione and cyclizing the latter under alkaline conditions to form 13fl-R -17-OR'-A -gonatriene-S-one which can be saponified under alkaline conditions to form the corresponding I3B-R -A -gQnatriene-17B-ol-3-one, which can be reacted with a compound selected from the group consisting of hydroxylamine and ot-lower alkyl hydroxylamines and their acid salts to form the corresponding 3-oximido -11 A -gonatriene-l7fi-ol, oxidizing the latter to form the corresponding 3-oximido 13B-R -A -gonatriene-17- one, reacting the latter with a lower alkyl metallic compound to form the corresponding 3-0Ximido l3B-R -17oclower a1kyl-A -gonatriene-17fl-ol and hydrolyzing the latter under acidic conditions to form a 13fl-R -17alower-alkyl-M' -gonatriene-l7p-ol-3-one which can be esterified in the 17-position with an acylating agent of an organic carboxylic acid having 1 to 18 carbon atoms, such as an acid anhydride or acid halide to form the corresponding 17,8-OR-13fi-R -17a-R -A -gonatriene- 3-one.

In the following example there is described a preferred embodiment to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiment.

EXAMPLE Preparation of 4-chlor0-17,8-benzoyloxy-13fl-methyl- A -gnatriene-3 -one While agitating at room temperature, 1 gm. of 17 6- benzoyl-oxy-l3fl-methyl-A -gonatriene-3-one was dissolved in 20 cc. of pyridine, and then 0.43 cc. of sulfuryl chloride was added very slowly and the agitation Was maintained for 30 minutes at 20 C. under atmosphere of nitrogen. The reaction mixture was then treated with water and extracted with methylene chloride. The extract was Washed with dilute hydrochloric acid, then with a saturated solution of sodium bicarbonate and finally with water until the wash waters were neutral. The solution was dried, evaporated under vacuum, and a residue was obtained which was subjected to chromatography through silica gel and eluted with methylene chloride containing 2% of acetone. The fraction thus obtained was evaporated to dryness under vacuum, then recrystallized under reflux from isopropyl ether-methanol mixture (1:1), then from isopropyl ether-acetone (1:1) to obtain 105 mg. of 4-chloro-l7fl-benzoyloxy-13/3-methyl A -gonatriene-3-one having a melting point of 192 C. and a specific rotation [a] =+392i2 (c.=0.5% in chloroform).

The product occurred in the form of prisms insoluble in water, dilute aqueous acids and alkalis, slightly soluble in alcohol and ether and soluble in acetone, benzene and chloroform.

Analysis. C H ClO molecular Weight=408.9. Calculated: C, 73.42%; H, 6.16%; Cl, 8.67%. Found: C, 73.3%; H, 6.1%; Cl, 8.7%.

Infrared spectra in chloroform:

Benzoyloxy group: 1,710 cm." 0 O emr G O 1,275 Oonjugated triene-one: C 0 1,670 em.- {1,550 cm.- I i 1,530 ems- EtOH {233 m e=18,800 Am 352 m =29,50O

Infrared spectra in chloroform:

Acetoxy function: 1,728 cm.-

1,250 errL- Conjugated trieneone: C 0 1,670 em.- 1,593 Cmr o 0 1,552 cmr 1,532 cmr EtoH A 351-352 m This compound is not described in the literature.

In an analogous manner, by the above mode of operation 13,8,17a-din1ethy1 n -gonatriene 17B-ol-3-one was reacted with sulfuryl chloride to obtain 4-chlor0-13 6, 17a-dimethyl n -gonatriene 17fi-ol-3-one having a melting point of 156 C. and a specific rotation (c.=0.5% in methanol).

This compound is not described in the literature.

Various modifications of the'process of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

1. A 4-ch1oro-A -gonatriene of the formula References Cited by the Examiner Beereboom et al.: J.A.C.S. 75, p. 3500-3505, pages 3500 and 3501 relied on (1953).

Mori: Chem. and Pharmaceutical Bull. 10 pp. 492432,

pages 429-430 relied on (1962).

References Cited by the Applicant L. Velluz et coll. [CR Acad. Sci. T. 257 (1963) p. 569-570].

LEWIS GOTTS, Primary Examiner. HENRY A. FRENCH, Assistant Examiner. 

1. A 4-CHLORO-$4,9,11-GONATRIENE OF THE FORMULA 